A short enantioselective synthesis of guggultetrol, a naturally occurring lipid

Article abstract of DOI:10.1016/j.tetasy.2010.02.019

An enantioselective synthesis of the naturally occurring lipid, guggultetrol, is described with an overall yield of 24% starting from commercially available l-pentadecanol in ten linear steps. The key chiral-inducing steps include a Sharpless asymmetric epoxidation of allylic alcohol and a dihydroxylation of an α,β-unsaturated ester.

Full text of DOI:10.1016/j.tetasy.2010.02.019

Tetrahedron: Asymmetry 21 (2010) 558–561
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Tetrahedron: Asymmetry
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A short enantioselective synthesis of guggultetrol, a naturally occurring lipid
*
Shyla George, Gurunath Suryavanshi, Arumugam Sudalai
Chemical Engineering and Process Development Division, National Chemical laboratory, Pashan Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective synthesis of the naturally occurring lipid, guggultetrol, is described with an overall
yield of 24% starting from commercially available l-pentadecanol in ten linear steps. The key chiral-
inducing steps include a Sharpless asymmetric epoxidation of allylic alcohol and a dihydroxylation of
Received 2 February 2010
Accepted 23 February 2010
Available online 13 April 2010
an a,b-unsaturated ester.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Asymmetric catalysis provides a practical, cost-effective, and
efficient procedure for the synthesis of bioactive natural products
containing multiple stereogenic centers. Tetrols, in particular, with
contiguous stereogenic centers are useful intermediates in the syn-
thesis of a number of biologically active compounds1 such as phy-
tosphingosines.2 For instance, guggultetrol 1 (Fig. 1), a naturally
occurring lipid isolated from the gum-resin of the tree Commiphoru
mukul (guggul)3 known in Ayurveda (the Indian traditional system
of medicine) is used in the treatment of arthritis, inflammation,
obesity, and disorders of lipid metabolism.4
Retrosynthetic analysis of 1 shows that guggultetrol 1 could be
prepared from the Sharpless asymmetric dihydroxylation of
,b-unsaturated ester 2. The initial stereogenic center could easily
be established by the Sharpless asymmetric epoxidation of allylic
alcohol 3, which would then be obtained from commercially avail-
able 1-pentadecanol 4 (Scheme 1).
Accordingly, the synthesis of guggultetrol 1 was undertaken
starting from 1-pentadecanol 4 (Scheme 2). The oxidation of alco-
hol 4 under Swern conditions7 followed by Wittig olefination of the
a
resulting aldehyde gave (E)-a,b-unsaturated ester 5 in 90% yield.
The unsaturated ester 5 was then reduced using DIBALH in CH2Cl2
to give the allylic alcohol 3 in 96% yield. The allylic alcohol 3 thus
obtained after the reduction was subjected to epoxidation using
Sharpless asymmetric epoxidation conditions,8 with (ꢀ)-diethyl
tartrate[(ꢀ)-DET], Ti(OiPr)4, and anhydrous TBHP as an oxidant to
give the chiral epoxy alcohol 6 in 89% yield and 98% ee (the enan-
tiomeric purity was determined by 1H NMR analysis of the corre-
sponding Mosher’s ester).
OH OH
OH
H29C14
OH
Figure 1. Guggultetrol 1.
9
There are only a few literature reports5 available for the synthe-
sis of guggultetrol 1; all of them have made use of a chiral pool ap-
proach for its asymmetric synthesis. For instance, in 1986, Kjer
et al.5a reported the first asymmetric total synthesis of 1 using
furanose as the chiral template. Later Sukh Dev et al.5b,c employed
The treatment of the epoxy alcohol 6 with I2 and PPh3 gave
epoxy iodide 7 which was then converted to the allylic alcohol 8
in 80% yield by subjecting 7 to reflux with NaI and Zn10 in MeOH.
The allylic alcohol 8 was then protected as its MOM ether 9 in 91%
yields by treating it with MOMCl in the presence of diisopropyleth-
ylamine as a base. The oxidative degradation of the MOM-pro-
tected allylic alcohol 9 was carried out as indicated in the
following sequence of reactions: (i) the olefin functionality in 9
was initially dihydroxylated (OsO4, NMO); (ii) the diol so formed
was subsequently cleaved upon treatment with NaIO4 which gave
the corresponding aldehyde; (iii) the crude aldehyde, being labile,
was immediately subjected to Wittig olefination to provide the
D
-mannitol and
of guggultetrol 1. Recently, Prasad et al.5d have described a stereo-
selective synthesis of guggultetrol 1 commencing from -(+)-tar-
D-xylose for elucidating the absolute configuration
L
taric acid derivative. As part of our research program aimed at
developing enantioselective synthesis of bioactive molecules,6 we
wish to report a short and efficient enantioselective synthesis of
guggultetrol 1, by employing Sharpless asymmetric epoxidation
of allylic alcohol as the chiral-inducing step (Scheme 2).
a,b-unsaturated ester 2 in 90% yield over three steps. The dihydr-
oxylation of the
a,b-unsaturated ester 2 was carried out under
the Sharpless asymmetric dihydroxylation (SAD) conditions,11
using catalytic amounts of OsO4, and K3Fe(CN)6 as a co-oxidant
* Corresponding author. Tel.: +91 20 25902174; fax: +91 20 25902676.
E-mail address: a.sudalai@ncl.res.in (A. Sudalai).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.019

S. George et al. / Tetrahedron: Asymmetry 21 (2010) 558–561
559
OMOM
OH OH
OEt
H29C14
OH
OH
H29C14
H29C14
O
OH
1
3
2
H29C14 - CH2OH
4
Scheme 1. Retrosynthetic analysis of guggultetrol 1.
O
c
a
b
H29C14
OH
H29C14
OH
H29C14
OEt
4
5
3
OMOM
OR
O
g
e
h
OEt
R
H29C14
H29C14
H29C14
O
6
7
8
9
2
R=OH
R=I
R=H
R=MOM
d
f
MOMO
29C14
OH
MOMO
OH
OH OH
j
i
OEt
OH
OH
H
H29C14
H
29C14
OH
O
OH
11
OH
1
10
Scheme 2. Reagents and conditions: (a) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 °C to 25 °C, 1 h; (ii) PPh3@CHCO2Et, benzene, reflux, 12 h, 90%; (b) DIBALH, CH2Cl2, ꢀ78 °C, 2 h,
96%; (c) (ꢀ)-DET, Ti(OiPr)4, TBHP, CH2Cl2, ꢀ20 °C, 24 h, 89%; (d) I2, PPh3, imidazole, ether/acetonitrile (3:1), 0 °C, 1 h, 83%; (e) Zn, NaI, MeOH, reflux, 6 h, 80%; (f) MOMCl,
DIPEA, CH2Cl2, 0 °C to 25 °C, 12 h, 91%; (g) (i) OsO4, 50% aq NMO, acetone/H2O (9:1), 25 °C, 12 h; (ii) NaIO4, CH2Cl2, 25 °C, 10 min; (iii) PPh3=CHCO2Et, benzene, 50 °C, 1 h, 90%;
(h) (DHQ)2-PHAL, K2CO3, K3Fe(CN)6, MeSO2NH2, t-BuOH/H2O (1:1), K2OsO4ꢂH2O (0.2 mol %), 0 °C, 5 h, 86%; (i) LiAlH4, THF, 0 °C to 25 °C, 5 h, 86%; (j) concd HCl, MeOH, 25 °C,
4 h, 78%.
in the presence of (DHQ)2-PHAL ligand to give the dihydroxylated
ester 10 in 86% yield (dr = 11:1). The reduction of the ester function
in 10 (LiAlH4, THF) followed by deprotection of the MOM group in
11 with concd HCl in methanol afforded guggultetrol 1 in 78% yield
AV-200, AV-400, and AV-500 NMR spectrometers. Elemental anal-
ysis was carried out on a Carlo Erba CHNS-O analyzer.
4.2. (E)-Ethylheptadec-2-enoate 5
{[a] [a]D = +11.4 (c 0.34, EtOH)} The
D = +12 (c 0.5, EtOH); lit.5a,b
spectral data of guggultetrol thus synthesized were identical in
all respects with those of the material isolated from the natural
source.
To a precooled (ꢀ78 °C) solution of (COCl)2 (3.63 mL, 40 mmol)
in CH2Cl2 (50 mL) was added DMSO (5.68 mL, 80 mmol) in CH2Cl2
(10 mL). The reaction mixture was stirred at ꢀ78 °C for 15 min,
then alcohol 4 (4.56 g, 20 mmol) was added in CH2Cl2 (30 mL).
The reaction mixture was stirred for 40 min at ꢀ78 °C followed
by the addition of Et3N (16.67 mL, 120 mmol). The mixture was
allowed to warm to 0 °C. After 30 min, the reaction mixture was
diluted with water and extracted with CH2Cl2 (3 ꢁ 100 mL) and
the combined organic phases were dried over anhyd Na2SO4 and
concentrated to give the crude aldehyde, which was immediately
used in the next step.
3. Conclusions
In conclusion, a practical and enantioselective total synthesis of
guggultetrol, a naturally occurring lipid possessing three contigu-
ous stereogenic centers, has been achieved starting from the read-
ily available 1-pentadecanol in 10 linear steps and with an overall
yield of 24.1% using Sharpless1 asymmetric epoxidation and
dihydroxylation as the key steps. The present synthesis constitutes
the first catalytic approach to the asymmetric synthesis of guggul-
tetrol 1.
To a solution of the above crude aldehyde in benzene (60 mL) was
added (ethoxycarbonylmethylene)triphenylphosphorane (7.66 g,
22 mmol) and heated at reflux for 12 h. Removal of the solvent under
reduced pressure provided the crude product which was then puri-
fied by column chromatography over silica gel using petroleum
ether/EtOAc (9:1) to give 5 (5.3 g, 90%) as a colorless oil. IR (CHCl3)
mmax 2924, 2853, 1724, 1655, 1465, 1367, 1309, 1264, 1178, 1045,
4. Experimental
4.1. General information
981 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.89 (t, J = 6.6 Hz, 3H),
;
1.26–1.33 (m, 27H), 2.13–2.24 (m, 2H), 4.18 (q, J = 7.0 Hz, 2H), 5.79
(td, J = 1.5, 15.6 Hz, 1H), 6.95 (td, J = 6.9, 13.8 Hz, 1H); 13C NMR
(50 MHz, CDCl3) d 14.1, 14.3, 22.7, 28.1, 29.2, 29.4, 29.5, 29.7, 31.9,
31.9, 32.2, 59.9, 121.3, 149.3, 166.5. Anal. Calcd for C19H36O2
(296.49):C, 76.97; H, 12.24. Found: C, 77.22; H, 12.01.
Solvents were purified and dried by standard procedures before
use; petroleum ether of boiling range 60–80 °C was used. Optical
rotations were measured using sodium D line on a JASCO-181 dig-
ital polarimeter. Infrared spectra were recorded on Shimadzu FTIR-
8400 spectrometer. 1H NMR and 13C MNR were recorded on Bruker

560
S. George et al. / Tetrahedron: Asymmetry 21 (2010) 558–561
4.3. (E)-Heptadec-2-en-1-ol 3
1H); 13C NMR (50 MHz, CDCl3): d 4.89, 14.18, 22.72, 25.92, 29.39,
29.53, 29.56, 29.69, 31.73, 31.95, 58.25, 62.46. Anal. Calcd for
C17H33IO (380.35): C, 53.68; H, 8.75. Found: C, 53.99; H, 8.56.
To a solution of 5 (2.67 g, 9 mmol) in dry CH2Cl2 (60 mL) at
ꢀ78 °C was added dropwise DIBALH (22.5 mL, 22.5 mmol, 1 M in
toluene) through a syringe. The reaction mixture was allowed to
warm to room temperature over 2 h, recooled to 0 °C, treated with
saturated sodium potassium tartrate solution, and stirred for 1 h.
The organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2 (3 ꢁ 50 mL). The combined organic extracts
were washed with water (3 ꢁ 50 mL) and brine, dried over anhyd
Na2SO4, and concentrated under reduced pressure. Silica gel col-
umn chromatography of the crude product using petroleum
ether/EtOAc (9:1) gave 3 (2.2 g, 96%) as a colorless solid. Mp:
41.8 °C; IR (CHCl3) mmax 3433, 3018, 2926, 2864, 1216, 767,
4.6. (R)-Heptadec-1-en-3-ol 8
A mixture of epoxy iodide 7 (2.09 g, 5.5 mmol), NaI (2.06 g,
13.75 mmol), and freshly activated zinc (16.5 g, 1.08 mmol) in
dry MeOH (25 mL) was refluxed for 6 h under a nitrogen atmo-
sphere. The solution was filtered and the residue was washed with
MeOH (2 ꢁ 25 mL). The combined filtrates were concentrated and
the residue was taken in ethyl acetate (50 mL), washed with water
(2 ꢁ 30 mL), brine (1 ꢁ 20 mL), dried over anhyd Na2SO4, and con-
centrated under reduced pressure. The crude compound was puri-
fied by column chromatography using petroleum ether/EtOAc
(9.5:0.5) to afford compound 8 (1.12 g, 80%) as a colorless solid.
669 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.87 (t, J = 6.7 Hz, 3H),
;
1.25–1.35 (m, 26H), 1.54 (br s, 1H), 4.05–4.08 (m 2H), 5.61–5.68
(m, 2H); 13C NMR (50 MHz, CDCl3): d 14.11, 22.69, 29.19, 29.23,
29.38, 29.54, 29.64, 29.71, 31.93, 32.24, 63.50, 128.96, 133.10.
Anal. Calcd for C17H34O (254.45): C, 80.24; H, 13.47. Found: C,
80.51; H, 13.19.
Mp: 42–44 °C; ½a 2D5
¼ ꢀ16:7 (c 0.6, CHCl3); IR (CHCl3) mmax 3427,
ꢃ
3307, 3018, 2926, 2864, 1465, 1458, 1217, 1018, 993, 927, 769,
669 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.87 (t, J = 6.7 Hz, 3H),
;
1.25–1.53 (m, 26H), 4.05–4.10 (m, 1H), 5.07–5.22 (m, 2H), 5.81–
5.89 (m, 1H); 13C NMR (50 MHz, CDCl3): d 14.14, 22.71, 25.37,
29.39, 29.65, 29.71, 31.95, 37.06, 73.18, 114.38, 141.44. Anal. Calcd
for C17H34O (254.45): C, 80.24; H, 13.47. Found: C, 79.95; H, 13.79.
4.4. [(2R,3R)-3-Tetradecyloxiran-2-yl]methanol 6
To a stirred suspension of powdered 4 Å molecular sieves (1 g)
in dry CH2Cl2 (30 mL), Ti(OiPr)4 (0.12 g, 0.44 mmol) was added un-
der a nitrogen atmosphere. The reaction mixture was cooled to
ꢀ20 °C and (ꢀ)-diethyl tartrate (0.13 g, 0.64 mmol) was added
4.7. Mosher’s ester of (R)-heptadec-1-en-3-ol
1H NMR (200 MHz, CDCl3) d 0.87 (t, J = 6.6 Hz, 3H), 1.25 (s, 26H),
2.78–2.84 (m, 1H), 2.93–3.00 (m, 1H), 3.56 (s, 3H), 4.22 (dd, J = 6.0,
11.9 Hz, 1H), 4.51 (dd, J = 3.54, 12.0 Hz, 1H), 7.38–7.43 (m, 3H),
7.50–7.54 (m, 2H).
and stirred for 10 min, after which allylic alcohol
3 (2.2 g,
8.5 mmol) dissolved in CH2Cl2 (20 mL) was added and stirred at
ꢀ20 °C for 30 min. To the above solution, anhyd tert-butyl hydro-
peroxide (1.5 g, 17 mmol) dissolved in hexane was added and stir-
red at ꢀ20 °C for 24 h. After completion of the reaction (monitored
by TLC), it was quenched with 10% aqueous solution of tartaric acid
(25 mL), after which stirring was continued for 1 h at ꢀ20 °C and
2 h at room temperature. The organic layer was separated, washed
with water, dried over anhyd Na2SO4, and concentrated under re-
duced pressure. The residue was diluted with ether (75 mL) and
stirred with 1 M NaOH (25 mL) for 1 h at 0 °C. The organic layer
was then separated, washed with brine solution, dried over anhyd
Na2SO4, and concentrated under reduced pressure. The crude com-
pound was purified by column chromatography using petroleum
ether/EtOAc (8:2) to afford compound 6 (2.0 g, 89%) as a colorless
4.8. (R)-3-(Methoxymethoxy)heptadec-1-ene 9
To a solution of the allylic alcohol 8 (0.76 g, 3 mmol) and diiso-
propylethylamine (0.78 g, 1.02 mL, 6 mmol) in dry CH2Cl2 (20 mL)
was added MOMCl (0.36 g, 0.39 mL, 5.5 mmol) under nitrogen over
5 min at 0 °C, and the mixture was allowed to warm to room tem-
perature and stirred overnight. After cooling to 0 °C, the reaction
was quenched with water and the reaction mixture was extracted
with CH2Cl2 (3 ꢁ 20 mL). The combined organic extracts were
washed with water (3 ꢁ 50 mL) and brine, dried over anhyd
Na2SO4, and concentrated under reduced pressure. Silica gel col-
umn chromatography of the crude product using petroleum ether
solid. Mp: 74–77 °C; ½a D25
ꢃ
¼ þ10 (c 0.6, CHCl3); IR (CHCl3) mmax
3462, 3020, 2926, 2854, 1710, 1363, 1216, 767, 669 cmꢀ1
;
1H
gave 9 (0.81 g, 91%) as a colorless liquid. ½a D25
ꢃ
¼ þ64 (c 1, CHCl3); IR
NMR (200 MHz, CDCl3): d 0.87 (t, J = 6.6 Hz, 3H), 1.25–1.56 (m,
26H), 2.86–2.96 (m, 2H), 3.54–3.66 (m, 1H), 3.89 (dddd, J = 2.3,
2.6, 5.5, 5.5 Hz, 1H); 13C NMR (50 MHz, CDCl3): d 14.16, 22.72,
25.98, 29.39, 29.44, 29.57, 29.59, 29.69, 31.58, 31.95, 55.94,
58.55, 61.67. Anal. Calcd for C17H34O2 (270.45): C, 75.50; H,
12.67. Found: C, 75.82; H, 12.39.
(CHCl3) mmax 3018, 2927, 2854, 1216, 1033, 929 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): d 0.88 (t, J = 6.8 Hz, 3H), 1.25–1.62 (m, 26H),
3.36 (s, 3H), 3.91–4.01 (m, 1H), 4.52 (d, J = 6.7 Hz, 1H), 4.69 (d,
J = 6.7 Hz, 1H), 5.14–5.30 (m, 2H), 5.57–5.74 (m, 1H); 13C NMR
(50 MHz, CDCl3): d 13.81, 22.38, 25.07, 29.07, 29.28, 29.32, 29.36,
29.39, 31.63, 35.14, 54.96, 76.02, 93.33, 116.57, 138.31. Anal. Calcd
for C19H38O2 (298.5): C, 76.45; H, 12.83. Found: C, 76.77; H, 12.58.
4.5. (2S,3R)-2-(Iodomethyl)-3-tetradecyloxirane 7
4.9. (R)-trans-Ethyl-4-(methoxymethoxy)octadec-2-enoate 2
To a stirred solution of epoxy alcohol 6 (1.89 g, 7 mmol) in dry
ether/acetonitrile (3:1, 40 mL) at 0 °C under a nitrogen atmosphere
were added imidazole (0.71 g, 10.5 mmol), triphenylphosphine
(2.75 g, 10.5 mmol), and iodine (2.67 g, 10.5 mmol) successively.
The mixture was stirred for 1 h at the same temperature, diluted
with cold ether (20 mL), and filtered through a sintered funnel.
The residue was washed with ether (350 mL) and concentrated
in vacuo. The crude compound was purified by column chromatog-
raphy using petroleum ether/EtOAc (9:1) to afford epoxy iodide 7
Osmium tetroxide (catalytic amount) and 50% aqueous N-meth-
ylmorpholine N-oxide (0.66 mL, 2.8 mmol) were added to a solu-
tion of MOM ether 9 (0.42 g, 1.4 mmol) in acetone (5 mL) at 0 °C.
After continuous stirring for 12 h at 25 °C, the reaction mixture
was diluted with CH2Cl2 (30 mL), dried over anhyd Na2SO4, and
concentrated to give the crude diol which was then directly taken
for the next step without purification.
To a vigorously stirred suspension of silica gel-supported NaIO4
reagent (3.0 g) in CH2Cl2 (5 mL) in a 25 mL round-bottomed flask
was added a solution of the crude vicinal diol in CH2Cl2 (5 mL).
The reaction was monitored by TLC until the disappearance of
the starting material. The mixture was filtered through a sintered
(2.2 g, 83%) as a colorless solid. Mp: 60–61 °C; ½a D25
¼ ꢀ20 (c 0.3,
ꢃ
CHCl3); IR (CHCl3) mmax 3018, 2927, 2854, 1216, 767, 669 cmꢀ1
;
1H NMR (200 MHz, CDCl3): d 0.87 (t, J = 6.8 Hz, 3H), 1.25–1.50
(m, 26H), 2.73–2.79 (m, 1H), 2.93–3.03 (m, 2H), 3.20–3.31 (m,

S. George et al. / Tetrahedron: Asymmetry 21 (2010) 558–561
561
glass funnel, and the silica gel was thoroughly washed with CH2Cl2
(3 ꢁ 10 mL). The solvent was evaporated under reduced pressure to
give the product aldehyde which was immediately treated with (eth-
oxycarbonylmethylene)triphenylphosphorane (0.48 g, 1.4 mmol) in
benzene (10 mL) and stirred at 50 °C for 1 h. Removal of the solvent
under reduced pressure provided the crude product which was then
purified by column chromatography over silica gel using petroleum
ether/EtOAc (9.5:0.5) to give 2 (0.38 g, 73%) as a colorless oil.
22.74, 25.26, 29.41, 29.62, 29.65, 29.71, 29.74, 29.77, 31.10,
31.98, 55.90, 65.22, 70.83, 74.49, 82.95, 97.60. Anal. Calcd for
C20H42O5 (362.54): C, 66.26; H, 11.68. Found: C, 65.95; H, 11.99.
4.12. Guggultetrol 1
To a stirred solution of the alcohol 10 (72 mg, 0.2 mmol) in
methanol (5 mL) was added concd HCl and stirred for 4 h and then
extracted with EtOAc (3 ꢁ 10 mL), washed with brine, dried over
anhyd Na2SO4, and concentrated under reduced pressure. Silica
gel column chromatography of the crude product using petroleum
ether/EtOAc (3:7) gave guggultetrol 1 (50 mg, 78%) as a colorless
½
a 2D5
ꢃ
¼ þ30 (c 0.8, CHCl3); IR (CHCl3, cmꢀ1
) mmax 3018, 2927, 2864,
2399, 1712, 1517, 1466, 1216, 1031, 927, 761, 669; 1H NMR
(200 MHz, CDCl3): d 0.87 (t, J = 6.6 Hz, 3H), 1.24–1.60 (m, 29H),
3.36 (s, 3H), 4.11–4.24 (m, 3H), 4.53–4.63 (m, 2H), 5.95 (dd, J = 1.2,
15.8 Hz, 1H), 6.78 (dd, J = 6.4, 15.7 Hz, 1H); 13C NMR (50 MHz,
CDCl3): d 14.17, 14.30, 22.73, 25.20, 29.41, 29.57, 29.65, 29.70,
29.73, 31.97, 34.96, 55.56, 60.36, 75.23, 94.58, 121.82, 147.99,
166.10. Anal. Calcd for C22H42O4 (370.57): C, 71.31; H, 11.42. Found:
C, 71.02; H, 11.73.
solid. Mp: 80–82 °C (lit.5a mp: 78–81 °C); ½a 2D5
¼ þ12 (c 0.5, EtOH)
ꢃ
{lit.5a,b
½
a 2D5
ꢃ
¼ þ11:4 (c 0.34, EtOH)}; IR (MeOH) mmax 3382, 2925,
2833, 1448, 1419, 1116, 1027 cmꢀ1 1H NMR (400 MHz, CD3OD)
;
d 0.88 (t, J = 6.5 Hz, 3H), 1.28–1.59 (s, 26H), 3.42 (dd, J = 3.7,
7.5 Hz, 1H), 3.50–3.81 (m, 4H); 13C NMR (100 MHz, CD3OD) d
14.4, 23.7, 26.9, 30.5, 30.7, 30.8, 33.1, 64.4, 73.5, 74.1, 74.3. Anal.
Calcd for C18H38O4 (318.49) C, 67.88; H, 12.03. Found: C, 67.59;
H, 12.34.
4.10. (2R,3R,4R)-Ethyl-2,3-dihydroxy-4-(methoxymethoxy)-
octadecanoate 10
To a mixture of K3Fe(CN)6 (0.59 g, 1.8 mmol), K2CO3 (0.25 g,
1.8 mmol), and (DHQ)2-PHAL (5 mg, 1 mol %), in t-BuOH/H2O
(1:1, 12 mL) cooled at 0 °C was added K2OsO4ꢂH2O (1 mg,
0.2 mol %) followed by methanesulfonamide (57 mg, 0.6 mmol).
After being stirred for 5 min at 0 °C, olefin 2 (0.22 g, 0.6 mmol)
was added in one portion. The reaction mixture was stirred at
0 °C for 5 h and then the reaction was quenched with solid sodium
sulfite (1 g). The stirring was continued for an additional 45 min,
and then the solution was extracted with EtOAc (3 ꢁ 20 mL). The
combined organic extracts were dried over sodium sulfate and
concentrated. Flash column chromatography of the crude product
using petroleum ether/EtOAc (7:3) as eluent gave the diol 10
Acknowledgments
S.G. thanks CSIR, New Delhi, for the award of research fellow-
ship The authors are thankful to Dr. B. D. Kulkarni, Head, CEPD,
for his constant support and encouragement.
References
1. For the stereoselective synthesis and application of tetrols see, (a) Iida, H.;
Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1986, 51, 3769–3771; (b) Yamazaki, N.;
Kibayashi, C. J. Am. Chem. Soc. 1989, 111, 1396–1408.
2. For a review on sphingolipid synthesis see: Howell, A. R.; So, R. C.; Richardson,
S. K. Tetrahedron 2004, 60, 11327–11347.
3. Isolation and assignment of absolute stereochemistry of guggultetrols see (a)
Patil, V. D.; Nayak, U. R.; Dev, S. Tetrahedron 1973, 29, 1595–1598; for a review
of guggul lipids see: (b) Urizar, N. L.; Moore, D. D. Annu. Rev. Nutr. 2003, 23,
303–313.
4. (a) Satyavati, G. V. Indian J. Med. Res. 1988, 87, 327–335; (b) Sastry, V. V. S. Bull.
Indian Inst. Hist. Med. 1976, 6, 102–116.
(0.2 g, 86%) as a colorless gum. ½a D25
¼ ꢀ18 (c 2, CHCl3); IR (CHCl3)
ꢃ
mmax 3417, 3018, 2927, 2854, 2399, 1736, 1216, 1126, 1029, 757,
669 cmꢀ1 1H NMR (200 MHz, CDCl3) d 0.88 (t, J = 6.8 Hz, 3H),
;
1.26–1.53 (m, 29H), 3.42 (s, 3H), 3.55–3.68 (m, 2H), 3.75–3.82
(m, 1H), 4.13–4.18 (m, 1H), 4.29 (q, J = 7.2 Hz, 2H), 4.62–4.76 (m,
2H); 13C NMR (50 MHz, CDCl3) d 14.08, 14.14, 22.65, 25.09,
29.33, 29.55, 29.63, 29.65, 31.31, 31.89, 55.79, 61.72, 71.02,
74.04, 82.51, 98.03, 172.99. Anal. Calcd for C22H44O6 (404.58) C,
65.31; H, 10.96. Found: C, 65.62;H, 10.69.
5. (a) Kjer, A.; Kjer, D.; Skrydstrup, T. Tetrahedron 1986, 42, 1439–1448; (b)
Kumar, V.; Dev, S. Tetrahedron 1987, 43, 5933–5948; (c) Dev, S. Pure Appl. Chem.
1989, 61, 353–356; (d) Prasad, K. R.; Chandrakumar, A. Tetrahedron 2007, 63,
1798–1805.
6. (a) George, S.; Narina, S. V.; Sudalai, A. Tetrahedron 2006, 62, 10202–10207; (b)
Narina, S. V.; Sudalai, A. Tetrahedron Lett. 2006, 47, 6799–6802; (c) Kotkar, S. P.;
Sudalai, A. Tetrahedron: Asymmetry 2006, 17, 1738–1742; (d) Kotkar, S. P.;
Sudalai, A. Tetrahedron Lett. 2006, 47, 6813–6815; (e) Narina, S. V.; Talluri, S. K.;
George, S.; Sudalai, A. Tetrahedron Lett. 2007, 48, 65–68; (f) George, S.; Narina, S.
V.; Sudalai, A. Tetrahedron Lett. 2007, 48, 1375–1378; (g) George, S.; Sudalai, A.
Tetrahedron: Asymmetry 2007, 18, 975–981; (h) Kotkar, S. P.; Suryavanshi, G. S.;
Sudalai, A. Tetrahedron: Asymmetry 2007, 18, 1795–1798; (i) Talluri, S. K.;
Sudalai, A. Tetrahedron 2007, 63, 9758–9763; (j) George, S.; Sudalai, A.
Tetrahedron Lett. 2007, 48, 8544–8546.
7. For reviews on the Swern oxidation see: (a) Tidwell, T. T. Synthesis 1990, 857–
870; (b) Tidwell, T. T. Org. React. 1990, 39, 297–572.
8. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–5976; (b) Gao,
Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B. J. Am.
Chem. Soc. 1987, 109, 5765.
4.11. (2S,3R,4R)-4-(Methoxymethoxy)octadecane-1,2,3-triol 11
A solution of ester 10 (0.16 g, 0.4 mmol) in THF (5 mL) was
added to a stirred slurry of LiAlH4 (47 mg, 1.2 mmol) in THF
(5 mL). After being stirred for 5 h at 25 °C, the reaction was care-
fully quenched with water. The reaction mixture was then ex-
tracted with EtOAc (2 ꢁ 100 mL) and the combined organic
phases were dried over anhyd Na2SO4 and concentrated to give
the crude product, which was then purified by column chromatog-
raphy using petroleum ether/EtOAc (4:6) to give the triol 11
(125 mg, 86%) as a colorless oil. ½a D25
¼ ꢀ40 (c 0.4, CHCl3); IR
ꢃ
9. Corey, E. J.; Pyne, S. G.; Su, W.-G. Tetrahedron Lett. 1983, 24, 4883–4886.
10. Nicolaou, K. C.; Duggan, M. E.; Ladduwahetty, T. Tetrahedron Lett. 1984, 25,
2069–2072.
11. (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 448–451; (b)
Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–
2547.
(CHCl3) mmax 3411, 3018, 2926, 2854, 2399, 1216, 1031, 927, 767,
669 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.87 (t, J = 6.7 Hz, 3H),
;
1.24–1.38 (m, 23H), 1.47–1.74 (m, 3H), 3.41 (s, 3H), 3.51–3.84
(m, 5H), 4.63–4.74 (m, 2H); 13C NMR (50 MHz, CDCl3): d 14.19,